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Hereditary Paraganglioma-Pheochromocytoma Syndromes.


Kirmani S1, Young WF2.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2008 May 21 [updated 2014 Nov 6].

Author information

Associate Professor of Pediatrics, Chair, Department of Pediatrics & Child Health, Aga Khan Unversity, Karachi, Pakistan
Professor of Medicine, Chair, Division of Endocrinology, Mayo Clinic, Rochester, Minnesota



Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.


The diagnosis of hereditary PGL/PCC syndromes is based on physical examination, family history, imaging studies, biochemical testing, and molecular genetic testing. SDHA, SDHB, SDHC and SDHD are four nuclear genes that encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). A fifth nuclear gene, SDHAF2 (also known as SDH5) encodes a protein that appears to be required for flavination of another SDH subunit, SDHA. These are collectively known as the SDHx genes. Pathogenic variants in MAX predispose to PCC; a subset of individuals with pathogenic variants in MAX will also develop PGL. KIF1B,EGLN1 (formerly known as PHD2), IDH1, and FH have been reported to be associated with hereditary PGL/PCC, but their clinical significance is still unclear.


Treatment of manifestations: For secretory tumors including pheochromocytomas, antagonism of catecholamine excess with pharmacologic adrenergic receptor blockade followed by surgery. For nonsecretory skull base and neck paragangliomas, surgical resection if feasible. PGL/PCCs identified in individuals known to have SDHB pathogenic variants require resection promptly because of the high risk for malignant transformation. Prevention of secondary complications: Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, catecholamine hypersecretion, and malignant transformation. Surveillance: Beginning at age ten years or at least ten years before the earliest age at diagnosis in the family, individuals at risk for hereditary PGL/PCC syndromes need to begin lifelong biochemical and clinical surveillance for signs and symptoms of PGL/PCC. In individuals who have germline pathogenic variants in genes associated with PGL/PCC, MRI may be the preferable imaging modality to detect new or recurring tumors. Agents/circumstances to avoid: Hypoxia, cigarette smoking. Evaluation of relatives at risk: First-degree relatives (age ≥10 years) of an individual with a known SDHA, SDHB, SDHC,SDHD, SDHAF2, or MAX pathogenic variant should be offered molecular genetic testing to clarify their genetic status to improve diagnostic certainty and reduce the need for costly screening procedures in those who have not inherited the pathogenic variant.


The hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Pathogenic variants in SDHD (PGL1) demonstrate parent-of-origin effects and generally cause disease only when the pathogenic variant is inherited from the father. Initial data suggest that pathogenic variants in SDHAF2 (PGL2) and MAX exhibit parent-of-origin effects similar to those of pathogenic variants in SDHD. A proband with a hereditary PGL/PCC syndrome may have inherited the pathogenic variant from a parent or have a de novo pathogenic variant; the proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with a hereditary PGL/PCC syndrome has a 50% chance of inheriting the pathogenic variant. An individual who inherits a SDHD pathogenic variant from his/her mother is at a low but not negligible risk of developing disease; each of his/her offspring is at a 50% risk of inheriting the pathogenic variant. An individual who inherits an SDHD pathogenic variant from his/her father is at high risk of manifesting paragangliomas and, to a lesser extent, pheochromocytomas. If the pathogenic variant in the family is known, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

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